Phase-amplitude coupling

Native Oscillations

Native Oscillations

Propofol effects

• Decreases H-current conductance ($\downarrow \bar g_H$):
  • The H-current is a very slow, depolarizing current that is hyperpolarization-activated (weird, right?)
• Decreases Background Excitation ($\downarrow I_{applied}$):
  • This hyperpolarizes the system to mimic a loss of brainstem input
• Increases $GABA_A$ inhibition:
  • Increases max synaptic conductance ($\uparrow \bar g_{GABA_A}$)
  • Increases decay time constant ($\uparrow \tau_{GABA_A}$)

Original hypothesis

Our model network

Sustained alpha NOT natural

Detail: $T_{window}$ is critical

$GABA_A$ induces sustained alpha

Detail: Propofol alpha mechanism

Sustained alpha summary

• $GABA_A$ potentiation is the critical factor for sustained alpha!
• Sustained alpha does NOT occur normally
• $GABA_A$ potentiation uses spindling machinery (like $T_{window}$) to create sustained alpha
• Note that we have ONLY simulated an isolated thalamus so far

Recall: SWO

Recall: Our model network

Trough-max

Peak-max

Transition example

Alpha-SWO Coupling summary

• Overall thalamic hyperpolarization is the critical factor for switching between trough-max and peak-max!
• $GABA_A$ potentiation is required for any coupling, but cannot transform between PAC regimes!
• Given SWO UP/DOWN transitions coming from cortex to thalamus,
  • trough-max alpha CAN be generated during DOWNs by the thalamus independently!
  • peak-max alpha CAN be generated during DOWNs by the thalamus independently as well, or in combination with corticothalamic spikes

Overall Modeling Conclusions

• $GABA_A$ potentiation is the critical factor for sustained alpha, implying a thalamic component of propofol PAC
• Once there is sustained alpha, thalamic hyperpolarization is the critical factor for switching between trough-max and peak-max, implying a brainstem component of propofol PAC
• You need both to get switching between peak-max and trough-max in thalamocortical output

Overall Modeling Conclusions

• Thus, our initial model was ONLY insufficient in that there are other constraints; you also need:
  • $GABA_A$ increase
  • $\bar g_H$ decrease

Simulation Code

Our lab uses and develops the DynaSim Simulator originally created by Jason Sherfey. All the code necessary to run these simulations is available on GitHub here!